rs45554035

Variant names:

• chr9-128179098-T-C
• rs45554035
• NM_001131016.2:c.1109A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001131016.2(CIZ1):​c.1109A>G​(p.Glu370Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,613,978 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (32 hom., cov: 33)
  • Exomes 𝑓: 0.00088 (23 hom.)
• Consequence: CIZ1 NM_001131016.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.394
• Publications: 5 publications found

Genes affected

CIZ1 (HGNC:16744): (CDKN1A interacting zinc finger protein 1) The protein encoded by this gene is a zinc finger DNA binding protein that interacts with CIP1, part of a complex with cyclin E. The encoded protein may regulate the cellular localization of CIP1. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

CIZ1 Gene-Disease associations (from GenCC):

• dystonia 23

  Inheritance: Unknown Classification: MODERATE Submitted by: Genomics England PanelApp
• inherited dystonia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002975911).
• BP6: Variant 9-128179098-T-C is Benign according to our data. Variant chr9-128179098-T-C is described in ClinVar as Benign. ClinVar VariationId is 455980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00902 (1374/152322) while in subpopulation AFR AF = 0.0318 (1321/41570). AF 95% confidence interval is 0.0304. There are 32 homozygotes in GnomAd4. There are 631 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1374 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001131016.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIZ1	NM_001131016.2	MANE Select	c.1109A>G	p.Glu370Gly	missense	Exon 8 of 17	NP_001124488.1	Q9ULV3-1
	CIZ1	NM_001257975.2		c.1199A>G	p.Glu400Gly	missense	Exon 8 of 18	NP_001244904.1	F5H2X7
	CIZ1	NM_012127.3		c.1109A>G	p.Glu370Gly	missense	Exon 8 of 17	NP_036259.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIZ1	ENST00000372938.10	TSL:1 MANE Select	c.1109A>G	p.Glu370Gly	missense	Exon 8 of 17	ENSP00000362029.5	Q9ULV3-1
	CIZ1	ENST00000415526.5	TSL:1	c.875A>G	p.Glu292Gly	missense	Exon 6 of 15	ENSP00000398011.1	H0Y5D5
	CIZ1	ENST00000372954.5	TSL:1	c.1037A>G	p.Glu346Gly	missense	Exon 7 of 17	ENSP00000362045.1	Q9ULV3-3

Frequencies

GnomAD3 genomes AF: 0.00901 AC: 1371 AN: 152204 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00238 AC: 592 AN: 248740 AF XY: 0.00154

Gnomad AFR exome AF: 0.0331

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000539

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000875 AC: 1279 AN: 1461656 Hom.: 23 Cov.: 34 AF XY: 0.000703 AC XY: 511 AN XY: 727144

African (AFR) AF: 0.0322 AC: 1077 AN: 33478

American (AMR) AF: 0.00157 AC: 70 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111854

Other (OTH) AF: 0.00179 AC: 108 AN: 60390

GnomAD4 genome AF: 0.00902 AC: 1374 AN: 152322 Hom.: 32 Cov.: 33 AF XY: 0.00847 AC XY: 631 AN XY: 74486

African (AFR) AF: 0.0318 AC: 1321 AN: 41570

American (AMR) AF: 0.00255 AC: 39 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00290 Hom.: 18

Bravo AF: 0.00958

ESP6500AA AF: 0.0250 AC: 110

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00287 AC: 348

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Dystonic disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.39
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.044
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.035	D
Polyphen		0.98	D
Vest4		0.14
MVP		0.26
MPC		0.78
ClinPred		0.031	T
GERP RS		1.4
Varity_R		0.094
gMVP		0.12
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45554035; hg19: chr9-130941377;